C1q is a component of the CI complex of the classical complement pathway (R. B. Sim and K. B. M. Reid, Immunology Today 1991; 12:307-311). The biological functions of C1q are diverse, including initiation of the complement cascade for opsonization and cytolysis, and mediation of several different functions depending on the cell types expressing the C1q receptor. C1q enhances FcR and CR1-mediated phagocytosis in monocytes/macrophages (D. A. Bobak et al., Eur. J. Immunol. 1988; 18:2001-2007; D. A. Bobak et al., J. Immunol. 1987; 138:1150-1156), stimulates immunoglobulin production by B cells (K. R. Young et al., J. Immunol. 1991; 146:3356-3364), activates platelets to express αIIb/β3 integrins, P-selectin, and procoagulant activity (E. I. B. Peerschke et al., J. Exp. Med. 1993; 178:579-587; E. I. B. Peerschke et al., J. Immunol. 1994; 152:5896-5901), activates tumor cytotoxicity of macrophages (R. W. Leu et al., J. Immunol. 1990; 144:2281-2286), exerts anti-proliferative effects on T cell growth (A. Chen et al., J. Immunol. 1994; 153:1430-1440), and serves as a receptor for the Listeria monocytogenes invasion protein InIB Braun et al., EMBO J, 2000; 19: 1458-1466).
A 33 kilodalton (kD) receptor, designated gC1qR/p32 (and alternatively referred to as p32, and referred to herein as gC1qR/p32), which binds to the globular head of C1q molecules has been identified, cloned and sequenced (B. Ghebrehiwet et al., J. Exp. Med. 1994; 179:1809-1821; E. I. B. Peerschke et al., J. Immunol. 1994; 152:5896-5901; A. Chen et al., J. Immunol. 1994; 153: 1430-1440). The crystal structure of gC1qR/p32 has also been solved (Jiang et al. PNAS, 1999; 96, 3572-3577). Another 60 kD receptor, designated cC1qR, binds to the amino-terminal collagen-like region of C1q (B. Ghebrehiwet, Behring Inst. Mitt. 1989; 84:204-215; A. Chen et al., J. Immunol. 1994; 153:1430-1440). Based on the detection of gC1q-R mRNA by polymerase chain reaction (PCR) amplification and gC1q-R protein expression by immunochemical methods, this receptor was found to exist on a large number of different cell types, e.g. B cells, T cells, monocytes/macrophages, neutrophils, eosinophils, fibroblasts, platelets, endothelial cells, liver cells, neural cells and smooth muscle cells. The gC1q-R protein is over-expressed in tumor cells and tumors (Rubinstein et al., Int J Cancer, 2004; 110: 741-750).
The endothelial lining of blood vessels is highly diversified. Many, and perhaps all, normal tissues impart a tissue-specific “signature” on their vasculature, and tumor vessels differ from normal vessels both in morphology and molecular composition (Ruoslahti E. Specialization of tumor vasculature. Nat Rev Cancer 2002; 2:83-90). Tumors induce angiogenesis to support expansive growth (Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100:57-70) and many of the changes in tumor vessels are angiogenesis related (Brooks P G et al. J Reprod Med 1994; 39:755-60; Christian et al. J Cell Biol 2003; 163:871-8; Ferrara et al. Nat Med 1999; 5: 1359-64; Pasqualini et al Cancer Res 2000; 60: 722-7). Moreover, tumor blood vessels have tumor type-specific and, in some stages, stage-specific characteristics; in vivo screening of phage libraries has yielded distinct sets of homing peptides selectively recognizing angiogenic signatures in two transgenic mouse models of organ-specific tumorigenesis. Homing peptides can also distinguish the angiogenic blood vessels of premalignant lesions from those of fully malignant lesions in the same tumor. Lymphatic vessels in tumors also carry specific markers that distinguish tumor lymphatics from lymphatics in normal tissues (Laakkonen et al., Nat Med 2002; 8: 751-755; Laakkonen et al., Proc Natl Acad Sci USA, 2004; 101: 9381-9386: Zhang et al., Cancer Res, 2006; 66: 5696-9706). Tumor blood vessels and lymphatics provide important targets for tumor therapy. Destroying tumor blood vessels or preventing their growth suppresses tumor growth, whereas tumor lymphatics are not essential for tumor growth, but destroying them reduces metastasis (Saharinen et al. Trends Immunol 2004; 25:387-95).
The elevated expression of gC1qR/p32 in tumors and the findings reported here show there is a need for new therapeutic strategies for selectively targeting gC1q receptors (gC1qR, alternatively referred to in the art and herein as p32, and throughout as gC1qR/p32). The present invention satisfies this need by providing molecules that selectively interact with gC1qR/p32, and which are suitable for selectively targeting chemotherapeutic drugs, gene therapy vectors or other agents to the appropriate tissue. Related advantages also are provided.